183-OR: Overcoming Immunological Barriers for “Off-the-Shelf” iPSC-Derived Islets
Bibliographic record
Abstract
Improved differentiation protocols allow large-scale generation of induced pluripotent stem cell (iPSC) -derived islets. In order to make allogeneic “off-the-shelf” islets clinically useful and avoid rejection absent immunosuppression (IS) , they need to evade host immune responses, a property we refer to as being “hypoimmune.” Rhesus macaque (NHP) iPSCs were engineered to knock-out function of MHC class I and II and overexpress CD47 (HIP iPSCs) . HIP iPSCs and unedited iPSCs (wt iPSCs) were transduced to express luciferase and transplanted IM into four allogeneic NHPs per group. There was a strong IFN-γ ELISpot T cell response 1 week after wt iPSC transplantation, and increased production of wt-iPSC specifc IgM antibodies (Ab) and IgG Abs. At all time points tested (up to 12 weeks) , PBMCs killed wt iPSCs via direct and Ab-mediated cellular cytotoxicity. Furthermore, serum from NHPs killed wt iPSCs via complement-dependent cytotoxicity. In contrast, NHPs that received HIP iPSCs showed no measurable immune response against HIP iPSCs at all time points. After 6 weeks, NHPs initially receiving wt iPSCs were injected with HIP iPSCs. Although the NHPs maintained their strong immune response against wt iPSCs, they did not mount any response against HIP iPSCs. NHPs receiving HIP iPSCs first developed a strong cellular and Ab-response against the subsequently injected wt iPSCs but continued to have no reactivity against HIP iPSCs. Bioluminescence imaging in vivo revealed rejection of all wt iPSC grafts in both groups within 2-3 weeks after transplantation, while all HIP iPSC grafts survived the study period of 16 weeks. As a step to extending these studies to human iPSCs, we created human HIP iPSCs. We were able to differentiate these human HIP iPSCs into functional HIP islet cells that evaded host immune responses. This work suggests that HIP modifications do not impact islet cell differentiation or function. These data support the development of allogeneic HIP islets for the treatment of patients with T1DM. Disclosure X.Hu: None. F.Wells: None. T.Mcgill: Employee; Sana Biotechnology Inc. M.Rukstalis: Employee; Sana Biotechnology Inc. C.Gattis: None. R.Basco: None. J.R.Millman: Consultant; Sana Biotechnology Inc., Other Relationship; Sana Biotechnology Inc., Vertex Pharmaceuticals Incorporated, Research Support; Sana Biotechnology Inc., Stock/Shareholder; Salentra Biosciences. S.Schrepfer: Other Relationship; Sana Biotechnology Inc. K.White: None. A.G.Olroyd: None. R.Dejesus: None. A.Dominguez: Employee; Sana Biotechnology Inc. W.E.Dowdle: Employee; Sana Biotechnology Inc., Stock/Shareholder; Sana Biotechnology Inc. E.Y.L.Chu: None. A.Friera: None. C.Young: Employee; Sana Biotechnology Inc.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".